WARNING: SERIOUS GASTROINTESTINAL ADVERSE REACTIONS

Infrequent but serious gastrointestinal adverse reactions have been reported with the use of alosetron hydrochloride tablets. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization, and rarely, blood transfusion, surgery, and death.

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Alosetron hydrochloride tablets are indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have not responded adequately to conventional therapy [see Indications and Usage (1)].

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Alosetron hydrochloride tablets should be discontinued immediately in patients who develop constipation or symptoms of ischemic colitis. Patients should immediately report constipation or symptoms of ischemic colitis to their prescriber. Alosetron hydrochloride tablets should not be resumed in patients who develop ischemic colitis. Patients who have constipation should immediately contact their prescriber if the constipation does not resolve after alosetron hydrochloride tablets is discontinued. Patients with resolved constipation should resume alosetron hydrochloride tablets only on the advice of their treating prescriber [see Dosage and Administration (2.1), Warnings and Precautions (5.1), (5.2)].

These highlights do not include all the information needed to use ALOSETRON HYDROCHLORIDE TABLETS safely and effectively. See full prescribing information for ALOSETRON HYDROCHLORIDE TABLETS.
ALOSETRON HYDROCHLORIDE Tablets, for oral use
Initial U.S. Approval: 2000

WARNING: SERIOUS GASTROINTESTINAL ADVERSE REACTIONS

See full prescribing information for complete boxed warning

Infrequent but serious gastrointestinal adverse reactions have been reported with the use of Alosetron Hydrochloride Tablets. These events, including ischemic colitis and serious complications of constipation, have resulted in hospitalization and, rarely, blood transfusion, surgery, and death.

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Alosetron Hydrochloride Tablets are indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have not responded adequately to conventional therapy. (1)

WARNINGS AND PRECAUTIONS

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Serious Complications of Constipation: May occur in some patients without warning. Include obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia and in rare cases perforation and death have been reported. Risk is increased in patients who are elderly, debilitated, or taking medications that decrease bowel motility. (5.1)

had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and

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not responded adequately to conventional therapy.

Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following:

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frequent and severe abdominal pain/discomfort,

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frequent bowel urgency or fecal incontinence,

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disability or restriction of daily activities due to IBS.

Because of infrequent but serious gastrointestinal adverse reactions associated with alosetron hydrochloride tablets, the indication is restricted to those patients for whom the benefit-to-risk balance is most favorable.

Clinical studies have not been performed to adequately confirm the benefits of alosetron hydrochloride tablets in men.

2.1 Adult Patients

To lower the risk of constipation, alosetron hydrochloride tablets should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking alosetron hydrochloride tablets until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, alosetron hydrochloride tablets should be discontinued immediately.

Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day. Alosetron hydrochloride tablets should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day.

Alosetron hydrochloride tablets should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Alosetron hydrochloride tablets should not be restarted in patients who develop ischemic colitis.

Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow-up should be exercised if alosetron hydrochloride tablets are prescribed for these patients.

Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation; therefore, appropriate caution and follow-up should be exercised if alosetron hydrochloride tablets are prescribed for these patients [see Warnings and Precautions (5.1)].

2.2 Patients With Hepatic Impairment

Alosetron hydrochloride tablets is extensively metabolized by the liver, and increased exposure to alosetron hydrochloride tablets is likely to occur in patients with hepatic impairment. Increased drug exposure may increase the risk of serious adverse reactions. Alosetron hydrochloride tablets should be used with caution in patients with mild or moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment [see Contraindications (4)], and Use In Specific Populations (8.6)].

Alosetron Hydrochloride Tablets, 0.5 mg (0.562 mg alosetron HCl equivalent to 0.5 mg alosetron), are white to off-white, round biconvex tablets, debossed with 54 628 on one side and plain on the other side.

Alosetron Hydrochloride Tablets, 1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron), are white to off-white, round biconvex tablets, debossed with 54 974 on one side and plain on the other side.

4.3 Concomitant Use of Fluvoxamine

Concomitant administration of alosetron hydrochloride tablets with fluvoxamine are contraindicated. Fluvoxamine, a known strong inhibitor of CYP1A2, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold [see Drug Interactions (7.1)].

5.1 Serious Complications of Constipation

Some patients have experienced serious complications of constipation without warning.

Serious complications of constipation, including obstruction, ileus, impaction, toxic megacolon, and secondary bowel ischemia, have been reported with use of alosetron hydrochloride tablets during clinical trials. Complications of constipation have been reported with use of 1 mg twice daily and with lower doses. A dose response relationship has not been established for serious complications of constipation. The incidence of serious complications of constipation was approximately 0.1% (1 per 1,000 patients) in women receiving either alosetron hydrochloride tablets or placebo. In addition, rare cases of perforation and death have been reported from postmarketing clinical practice. In some cases, complications of constipation required intestinal surgery, including colectomy. Patients who are elderly, debilitated, or taking additional medications that decrease gastrointestinal motility may be at greater risk for complications of constipation.

5.2 Ischemic Colitis

Some patients have experienced ischemic colitis without warning.

Ischemic colitis has been reported in patients receiving alosetron hydrochloride tablets in clinical trials as well as during marketed use of the drug. In IBS clinical trials, the cumulative incidence of ischemic colitis in women receiving alosetron hydrochloride tablets was 0.2% (2 per 1,000 patients, 95% confidence interval 1 to 3) through 3 months and was 0.3% (3 per 1,000 patients, 95% confidence interval 1 to 4) through 6 months. Ischemic colitis has been reported with use of 1 mg twice daily and with lower doses. A dose-response relationship has not been established. Ischemic colitis was reported in one patient receiving placebo. The patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking alosetron hydrochloride tablets for longer than 6 months.

Alosetron hydrochloride tablets should be discontinued immediately in patients with signs of ischemic colitis such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Because ischemic colitis can be life-threatening, patients with signs or symptoms of ischemic colitis should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with alosetron hydrochloride tablets should not be resumed in patients who develop ischemic colitis.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patients With Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of alosetron hydrochloride tablets twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received alosetron hydrochloride tablets and occurred more frequently on alosetron hydrochloride tablets than on placebo. A statistically significant difference was observed for constipation in patients treated with alosetron hydrochloride tablets compared to placebo (p<0.0001).

Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with alosetron hydrochloride tablets [see Warnings and Precautions (5.1)]. In clinical studies constipation was reported in approximately 29% of patients with IBS treated with alosetron hydrochloride tablets 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p<0.0001). Eleven percent (11%) of patients treated with alosetron hydrochloride tablets 1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with alosetron hydrochloride tablets 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation. Among the patients treated with alosetron hydrochloride tablets 1 mg twice daily who reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment, with the median time to first report of constipation onset of 8 days. Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature, and resolved either spontaneously with continued treatment or with an interruption of treatment. However, serious complications of constipation have been reported in clinical studies and in postmarketing experience [see Boxed Warning and Warnings and Precautions (5.1)]. In Studies 1 and 2, 9% of patients treated with alosetron hydrochloride tablets reported constipation and 4 consecutive days with no bowel movement [see Clinical Studies (14.2)]. Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with alosetron hydrochloride tablets.

Hepatic: A similar incidence in elevation of ALT (>2-fold) was seen in patients receiving alosetron hydrochloride tablets or placebo (1% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase, and bilirubin) without jaundice in a patient receiving alosetron hydrochloride tablets was reported in a 12-week study. A causal association with alosetron hydrochloride tablets has not been established.

Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks. The adverse reactions in Table 2 were reported in 3% or more of patients who received alosetron hydrochloride tablets and occurred more frequently with alosetron hydrochloride tablets than with placebo. Other events reported in 3% or more of patients who received alosetron hydrochloride tablets and occurring more frequently with alosetron hydrochloride tablets than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches, and fatigue.

Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2. Gastrointestinal adverse reactions reported in 3% or more of patients who received alosetron hydrochloride tablets and occurring more frequently with alosetron hydrochloride tablets than with placebo included constipation (14% and 10% of patients taking alosetron hydrochloride tablets 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting, and flatulence. Other events reported in 3% or more of patients who received alosetron hydrochloride tablets and occurring more frequently with alosetron hydrochloride tablets than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral gastroenteritis, and cough.

Constipation: Constipation was the most frequent adverse reaction among women with severe diarrhea-predominant IBS represented in Table 2. There was a dose response in the groups treated with alosetron hydrochloride tablets in the number of patients withdrawn due to constipation (2% on placebo, 5% on 0.5 mg once daily, 8% on 1 mg once daily, and 11% on 1 mg twice daily). Among these patients with severe diarrhea-predominant IBS treated with alosetron hydrochloride tablets who reported constipation most (75%) reported one episode which occurred within the first 15 days of treatment and persisted for 4 to 5 days.

Other Events Observed During Clinical Evaluation of Alosetron Hydrochloride Tablets: During its assessment in clinical trials, multiple and single doses of alosetron hydrochloride tablets were administered, resulting in 11,874 subject exposures in 86 completed clinical studies. The conditions, dosages, and duration of exposure to alosetron hydrochloride tablets varied between trials, and the studies included healthy male and female volunteers as well as male and female patients with IBS and other indications.

In the listing that follows, reported adverse reactions were classified using a standardized coding dictionary. Only those events that an investigator believed were possibly related to alosetron hydrochloride tablets, occurred in at least 2 patients, and occurred at a greater frequency during treatment with alosetron hydrochloride tablets than during placebo administration are presented. Serious adverse reactions occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to treatment with alosetron hydrochloride tablets and occurring at a greater frequency in patients treated with alosetron hydrochloride tablets than placebo-treated patients are also presented.

In the following listing, events are categorized by body system. Within each body system, events are presented in descending order of frequency. The following definitions are used: infrequent adverse reactions are those occurring on one or more occasion in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring on one or more occasion in fewer than 1/1,000 patients.

Although the events reported occurred during treatment with alosetron hydrochloride tablets, they were not necessarily caused by it.

6.2 Postmarketing Experience

In addition to events reported in clinical trials, the following events have been identified during use of alosetron hydrochloride tablets in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to alosetron hydrochloride tablets.

In vivo data suggest that alosetron is primarily metabolized by cytochrome P450 (CYP) 1A2, with minor contributions from CYP3A4 and CYP2C9. Therefore, inducers or inhibitors of these enzymes may change the clearance of alosetron.

7.1 CYP1A2 Inhibitors

Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg/day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. Concomitant administration of alosetron and fluvoxamine is contraindicated [see Contraindications (4.3)].

Concomitant administration of alosetron and moderate CYP1A2 inhibitors, including quinolone antibiotics and cimetidine, has not been evaluated, but should be avoided unless clinically necessary because of similar potential drug interactions.

7.2 CYP3A4 Inhibitors

Ketoconazole is a known strong inhibitor of CYP3A4. In a pharmacokinetic study, 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days, with coadministration of alosetron 1 mg on the last day. Ketoconazole increased mean alosetron plasma concentrations (AUC) by 29%. Caution should be used when alosetron and ketoconazole are administered concomitantly. Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions. The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known.

7.3 Other CYP Enzymes

In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 3A4, 2C9, or 2C19. In vitro at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1 mg dose, alosetron inhibited CYP enzymes 1A2 (60%) and 2E1 (50%). In an in vivo metabolic probe study, alosetron did not inhibit CYP2E1 but did produce 30% inhibition of both CYP1A2 and N-acetyltransferase. Although not studied with alosetron, inhibition of N-acetyltransferase may have clinically relevant consequences for drugs such as isoniazid, procainamide, and hydralazine. The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed. Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents ethinyl estradiol and levonorgestrel (CYP3A4 substrates). A clinical interaction study was also conducted with alosetron and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted. The effects of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined. Based on the above data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the CYP enzymes 2C9, 2C19, or 2E1.

Alosetron does not appear to induce the major cytochrome P450 drug-metabolizing enzyme 3A. Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19. It is not known whether alosetron might induce other enzymes.

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, alosetron hydrochloride tablets should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

Alosetron and/or metabolites of alosetron are excreted in the breast milk of lactating rats. It is not known whether alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alosetron hydrochloride tablets are administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Use of alosetron hydrochloride tablets is not recommended in the pediatric population, based upon the risk of serious complications of constipation and ischemic colitis in adults.

8.5 Geriatric Use

In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults [see Warnings and Precautions (5.1)]. However, this effect was not consistently observed in men.

Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation therefore, appropriate caution and follow-up should be exercised if alosetron hydrochloride tablets is prescribed for these patients [see Warnings and Precautions (5.1)].

8.6 Hepatic Impairment

Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic impairment. Alosetron should not be used in patients with severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment.

A single 1 mg oral dose of alosetron was administered to 1 female and 5 male patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) and to 1 female and 2 male patients with severe hepatic impairment (Child-Pugh score of >9). In comparison with historical data from healthy subjects, patients with severe hepatic impairment displayed higher systemic exposure to alosetron. The female with severe hepatic impairment displayed approximately 14-fold higher exposure, while the female with moderate hepatic impairment displayed approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment [see Dosage and Administration (2.2), Contraindications (4)].

8.7 Renal Impairment

Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite pharmacokinetics and the effect of end-stage renal disease have not been assessed.

There is no specific antidote for overdose of alosetron hydrochloride tablets. Patients should be managed with appropriate supportive therapy. Individual oral doses as large as 16 mg have been administered in clinical studies without significant adverse reactions. This dose is 8 times higher than the recommended total daily dose. Inhibition of the metabolic elimination and reduced first pass of other drugs might occur with overdoses of alosetron hydrochloride tablets [see Drug interactions (7)].

The active ingredient in Alosetron Hydrochloride Tablets is alosetron hydrochloride (HCl), a potent and selective antagonist of the serotonin 5-HT3 receptor type. Chemically, alosetron is designated as 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, monohydrochloride. Alosetron hydrochloride is achiral and has the empirical formula C17H18N4O•HCl, representing a molecular weight of 330.8. Alosetron hydrochloride is a white to beige solid that has a solubility of 61 mg/mL in water, 42 mg/mL in 0.1M hydrochloric acid, 0.3 mg/mL in pH 6 phosphate buffer, and <0.1 mg/mL in pH 8 phosphate buffer. The chemical structure of alosetron is:

12.1 Mechanism of Action

Alosetron is a potent and selective 5-HT3 receptor antagonist. 5-HT3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit, and gastrointestinal secretions, processes that relate to the pathophysiology of IBS. 5-HT3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels, which results in the modulation of the enteric nervous system.

The cause of IBS is unknown. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, patients with IBS exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, alosetron reduced pain and exaggerated motor responses, possibly due to blockade of 5-HT3 receptors.

Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-β-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2 mg administered orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1 mg administered orally twice daily for 4 days, there was a significant decrease in urinary 6-β-hydroxycortisol excretion. However, there was no change in the ratio of 6-β-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown.

12.3 Pharmacokinetics

The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily.

Absorption: Alosetron was rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range, 30% to >90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1 mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurred at 1 hour. In young women, the mean peak plasma concentration was approximately 9 ng/mL, with a similar time to peak.

Plasma concentrations were 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men).

Food Effects: Alosetron absorption is decreased by approximately 25% by coadministration with food, with a mean delay in time to peak concentration of 15 minutes [see Dosage and Administration (2.1)].

Distribution: Alosetron demonstrates a volume of distribution of approximately 65 to 95 L. Plasma protein binding is 82% over a concentration range of 20 to 4,000 ng/mL.

Metabolism and Elimination: Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in patients with IBS confirmed that alosetron clearance is minimally influenced by doses up to 8 mg.

Renal elimination of unchanged alosetron accounts for only 13% of the dose. Renal clearance is approximately 112 mL/min.

A study with 14C-labeled alosetron in Caucasian males (n = 3) and females (n = 3) and an Asian male (n = 1) showed similar serum metabolite profiles. Unchanged alosetron was the major component in serum, with other metabolites being present at low concentrations, none amounting to more than 15% of the unmetabolized alosetron concentration. The circulating metabolites were identified as 6-hydroxy glucuronide, 6-hydroxy sulphate, 7-hydroxy sulphate, hydroxymethyl imidazole, and mono- and bis-oxygenated imidazole derivatives of alosetron. The metabolites are unlikely to contribute to the biological activity of alosetron. Of the circulating Phase I metabolites, only the hydroxymethyl imidazole has weak pharmacological activity, around 10-fold less potent than alosetron. Total recovery of radioactivity in the excreta was 85 ± 6%. The majority of the radiolabeled dose is excreted in the urine (74 ± 5%). The major urinary metabolites were the 6-hydroxy glucuronide and the mono- and bis-oxygenated imidazole derivatives of alosetron. 11 ± 4% of the radiolabeled dose was excreted in the feces with less than 1% of the dose being excreted as the unchanged alosetron.

Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non–CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism (62 to 97% of alosetron clearance) based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine [see Contraindications (4), Drug Interactions (7)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are about 60 to 160 times, respectively, the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK±) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats.

14.1 Dose-Ranging Study

Data from a dose-ranging study of women (n = 85) who received alosetron hydrochloride tablets 0.5 mg twice daily indicated that the incidence of constipation (14%) was lower than that experienced by women receiving 1 mg twice daily (29%). Therefore, to lower the risk of constipation, alosetron hydrochloride tablets should be started at a dosage of 0.5 mg twice a day. The efficacy of the 0.5 mg twice-daily dosage in treating severe diarrhea-predominant IBS has not been adequately evaluated in clinical trials [see Dosage and Administration (2.1)].

14.2 Efficacy Studies

Alosetron hydrochloride has been studied in women with IBS in five 12-week US multicenter, randomized, double-blind, placebo-controlled clinical studies.

Studies in Non-Constipated Women with Irritable Bowel Syndrome: Studies 1 and 2 were conducted in non-constipated women with IBS meeting the Rome Criteria1 for at least 6 months. Women with severe pain or a history of severe constipation were excluded. A 2-week run-in period established baseline IBS symptoms.

About two thirds of the women had diarrhea-predominant IBS. Compared with placebo, 10% to 19% more women with diarrhea-predominant IBS who received alosetron hydrochloride tablets had adequate relief of IBS abdominal pain and discomfort during each month of the study.

Studies in Women With Severe Diarrhea-Predominant Irritable Bowel Syndrome: Alosetron hydrochloride tablets is indicated only for women with severe diarrhea-predominant IBS [see Indications and Usage (1)]. The efficacy of alosetron hydrochloride tablets in this subset of the women studied in clinical trials is supported by prospective and retrospective analyses.

Prospective Analyses: Studies 3 and 4 were conducted in women with diarrhea-predominant IBS and bowel urgency on at least 50% of days at entry. Women receiving alosetron hydrochloride tablets had significant increases over placebo (13% to 16%) in the median percentage of days with urgency control.

The lower gastrointestinal functions of stool consistency, stool frequency, and sense of incomplete evacuation were also evaluated by patients’ daily reports. Stool consistency was evaluated on a scale of 1 to 5 (1 = very hard, 2 = hard, 3 = formed, 4 = loose, and 5 = watery). At baseline, average stool consistency was approximately 4 (loose) for both treatment groups. During the 12 weeks of treatment, the average stool consistency decreased to approximately 3.0 (formed) for patients who received alosetron hydrochloride tablets and 3.5 for the patients who received placebo in the 2 studies.

At baseline, average stool frequency was approximately 3.2 per day for both treatment groups. During the 12 weeks of treatment, the average daily stool frequency decreased to approximately 2.1 and 2.2 for patients receiving alosetron hydrochloride tablets and 2.7 and 2.8 for patients receiving placebo in the 2 studies.

There was no consistent effect upon the sense of incomplete evacuation during the 12 weeks of treatment for patients receiving alosetron hydrochloride tablets as compared to patients receiving placebo in either study.

Study 5 was conducted in women with severe diarrhea-predominant IBS and 1 or more of the following: frequent and severe abdominal pain or discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. To evaluate the proportion of patients who responded to treatment, patients were asked every 4 weeks to compare their IBS symptoms during the previous month of treatment with how they usually felt during the 3 months prior to the study using an ordered 7-point scale (substantially worse to substantially improved). A responder was defined as a subject who reported moderate or substantial improvement on this global improvement scale (GIS). At Week 12, all three groups receiving alosetron hydrochloride tablets had significantly greater percentages of GIS responders compared to the placebo group (43% to 51% vs. 31%) using a Last Observation Carried Forward (LOCF) analysis. It should be noted that approximately 4% of subjects in each alosetron hydrochloride tablets dose group who were classified as responders using this approach were observed only through week 4. At each of the 4 week intervals of the treatment phase, all three dosages of alosetron hydrochloride tablets provided improvement in the average adequate relief rate of IBS pain and discomfort, stool consistency, stool frequency, and sense of urgency compared with placebo.

Retrospective Analyses: In analyses of patients from Studies 1 and 2 who had diarrhea-predominant IBS and indicated their baseline run-in IBS symptoms were severe at the start of the trial, alosetron hydrochloride tablets provided greater adequate relief of IBS pain and discomfort than placebo. In further analyses of Studies 1 and 2, 57% of patients had urgency at baseline on 5 or more days per week. In this subset, 32% of patients on alosetron hydrochloride tablets had urgency no more than 1 day in the last week of the trial, compared with 19% of patients on placebo.

In Studies 3 and 4, 66% of patients had urgency at baseline on 5 or more days per week. In this subset, 50% of patients on alosetron hydrochloride tablets had urgency no more than 1 day in the last week of the trial, compared with 29% of patients on placebo. Moreover, in the same subset, 12% on alosetron hydrochloride tablets had urgency no more than 2 days per week in any of the 12 weeks on treatment compared with 1% of placebo patients.

Figure 1: Percent of Patients With Urgency on >5 Days/Week at Baseline Who Improved to No More Than 1 Day in the Final Week

In Studies 1 and 2, patient-reported subjective outcomes related to IBS were assessed by questionnaires obtained at baseline and week 12. Patients in the more severe subset who received alosetron hydrochloride tablets reported less difficulty sleeping, less tiredness, fewer eating problems, and less interference with social activities and work/main activities due to IBS symptoms or problems compared to those who received placebo. Change in the impact of IBS symptoms and problems on emotional and mental distress and on physical and sexual activity in women who received alosetron hydrochloride tablets were not statistically different from those reported by women who received placebo.

14.3 Long-Term Use

In a 48-week multinational, double-blind, placebo-controlled study, alosetron hydrochloride tablets 1 mg twice daily was evaluated in 714 women with non-constipated IBS. A retrospective analysis of the subset of women with severe diarrhea-predominant IBS (urgency on at least 10 days during the 2-week baseline period) was performed. Of the 417 patients with severe diarrhea-predominant IBS, 62% completed the trial.

Alosetron hydrochloride tablets (n = 198) provided a greater average rate of adequate relief of IBS pain and discomfort (52% vs. 41%) and a greater average rate of satisfactory control of bowel urgency (60% vs. 48%) compared with placebo (n = 219). Significant improvement of these symptoms occurred for most of the 48-week treatment period with no evidence of tachyphylaxis.

0.5 mg (0.562 mg alosetron HCl equivalent to 0.5 mg alosetron) tablets are supplied as white to off-white, round, biconvex tablets with product identification “54” over “628” debossed on one side and plain on the other site.

NDC 0054-0295-13: Bottle of 30 Tablets with child-resistant closures.

1 mg (1.124 mg alosetron HCl equivalent to 1 mg alosetron) tablets are supplied as white to off-white, round, biconvex tablets with product identification “54” over “974” debossed on one side and plain on the other site.

Patients should be fully counseled on and understand the risks and benefits of alosetron hydrochloride tablets before an initial prescription is written. The patient may be educated by the prescriber or a healthcare provider under a prescriber’s direction.

Prescribers must:

•

counsel patients for whom alosetron hydrochloride tablets are appropriate about the benefits and risks of alosetron hydrochloride tablets and discuss the impact of IBS symptoms on the patient’s life.

•

review the Medication Guide, which outlines the benefits and risks of alosetron hydrochloride tablets, and instruct the patient to read it carefully. Answer all questions the patient may have about alosetron hydrochloride tablets. The complete text of the Medication Guide is printed at the end of this document.

Additional copies of the Medication Guide are available by contacting West-Ward Pharmaceuticals Corp. at 1-800-962-8364.

Patients who are prescribed alosetron hydrochloride tablets should be instructed to:

•

read the Medication Guide before starting alosetron hydrochloride tablets and each time they refill their prescription.

•

not start taking alosetron hydrochloride tablets if they are constipated.

•

immediately discontinue alosetron hydrochloride tablets and contact their prescriber if they become constipated, or have symptoms of ischemic colitis such as new or worsening abdominal pain, bloody diarrhea, or blood in the stool. Contact their prescriber again if their constipation does not resolve after discontinuation of alosetron hydrochloride tablets. Resume alosetron hydrochloride tablets only if their constipation has resolved and after discussion with and the agreement of their treating prescriber.

•

stop taking alosetron hydrochloride tablets and contact their prescriber if alosetron hydrochloride tablets does not adequately control IBS symptoms after 4 weeks of taking 1 mg twice a day.

Before using alosetron hydrochloride tablets for the first time, you should:

•

Understand that alosetron hydrochloride tablets have serious risks for some people.

•

Read and follow the directions in this Medication Guide.

Carefully read the Medication Guide you get with each refill for alosetron hydrochloride tablets. There may be new information. This Medication Guide does not take the place of talking with your doctor.

1. What is the most important information I should know about alosetron hydrochloride tablets?

A. Alosetron hydrochloride tablets are a medicine only for some women with severe chronic irritable bowel syndrome (IBS) whose:

•

main problem is diarrhea and

•

IBS symptoms have not been helped enough by other treatments.

B. Some patients have developed serious bowel side effects while taking alosetron hydrochloride tablets. Serious bowel (intestine) side effects can happen suddenly, including the following.

1. Serious complications of constipation: About 1 out of every 1,000 women who take alosetron hydrochloride tablets may get serious complications of constipation. These complications may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death. People who are older, who are weak from illness, or who take other constipating medicines may be more likely to have serious complications of constipation with alosetron hydrochloride tablets.

To lower your chances of getting serious complications of constipation, do the following:

•

If you are constipated, do not start taking alosetron hydrochloride tablets.

•

If you get constipated while taking alosetron hydrochloride tablets, stop taking it right away and call your doctor.

•

If your constipation does not get better after stopping alosetron hydrochloride tablets, call your doctor again.

•

If you stopped taking alosetron hydrochloride tablets, do not start taking alosetron hydrochloride tablets again
unless your doctor tells you to do so.

2. Ischemic colitis (reduced blood flow to the bowel): About 3 out of every 1,000 women who take alosetron hydrochloride tablets over a 6-month period may get a serious problem where blood flow to parts of the large bowel is reduced. This is called ischemic colitis. The chance of getting ischemic colitis when you take alosetron hydrochloride tablets for more than 6 months is not known. Ischemic colitis may lead to a hospital stay and, in rare cases, blood transfusions, surgery, and death.

Alosetron hydrochloride tablets may be right for you if all of these things are true about you:

•

Your doctor has told you that your symptoms are due to IBS.

•

Your IBS bowel problem is diarrhea.

•

Your IBS has lasted for 6 months or longer.

•

You tried other IBS treatments and they did not give you the relief you need.

•

Your IBS is severe.

You can tell if your IBS is severe if at least 1 of the following is true for you:

•

You have lots of painful stomach cramps or bloating.

•

You often cannot control the need to have a bowel movement, or you have “accidents” where your underwear gets dirty from diarrhea or bowel movements.

•

You cannot lead a normal home or work life because you need to be near a bathroom.

Enough testing has not been done to confirm alosetron hydrochloride tablets works in men or children under age 18.

2. What are alosetron hydrochloride tablets?

Alosetron hydrochloride tablets are a medicine only for some women with severe chronic IBS whose:

•

main problem is diarrhea and

•

IBS symptoms have not been helped enough by other treatments.

Alosetron hydrochloride tablets does not cure IBS, and it may not help every person who takes it. For those who are helped, alosetron hydrochloride tablets reduces lower stomach area (abdominal) pain and discomfort, the sudden need to have a bowel movement (bowel urgency), and diarrhea from IBS. If you stop taking alosetron hydrochloride tablets, your IBS symptoms may return within 1 or 2 weeks to what they were before you started taking alosetron hydrochloride tablets.

Alosetron hydrochloride tablets are not recommended for children.

3. Who should not take alosetron hydrochloride tablets?

Alosetron hydrochloride tablets are not right for everyone. Do not take alosetron hydrochloride tablets if any of the following apply to you:

•

Your main IBS problem is constipation or you are constipated most of the time.

•

You have had a serious problem from constipation. If you are constipated now, do not start taking alosetron hydrochloride tablets.

•

You have had serious bowel blockages.

•

You have had blood flow problems to your bowels, such as ischemic colitis.

•

You have had blood clots.

•

You have had Crohn’s disease, ulcerative colitis, diverticulitis, or severe liver disease.

•

You do not understand this Medication Guide or you are not willing to follow it.

•

You are taking fluvoxamine (LUVOX®).

4. What should I talk about with my doctor before taking alosetron hydrochloride tablets?

Talk with your doctor:

•

about the possible benefits and risks of alosetron hydrochloride tablets.

•

about how much of a problem IBS is in your life and what treatments you have tried.

•

about any other illnesses you have and medicines you take or plan to take. These include prescription and non-prescription medicines, supplements, and herbal remedies. Certain illnesses and medicines can increase your chance of getting serious side effects while taking alosetron hydrochloride tablets. Other medicines may interact with how the body handles alosetron hydrochloride tablets.

•

about any allergies that you have. See the end of the Medication Guide for a complete list of ingredients in alosetron hydrochloride tablets.

•

if you are pregnant, planning to get pregnant, or breastfeeding.

5. How should I take alosetron hydrochloride tablets?

•

Take alosetron hydrochloride tablets exactly as your doctor prescribes it. You can take alosetron hydrochloride tablets with or without food.

•

Begin with 0.5 mg two times a day for 4 weeks to see how alosetron hydrochloride tablets affects you. You and your doctor may decide that you should keep taking this dose if you are doing well.

If you try 0.5 mg two times a day for 4 weeks, it may not control your symptoms. If you do not get constipation or other side effects from alosetron hydrochloride tablets, your doctor may increase your dose up to 1 mg two times a day.

•

If 1 mg two times a day does not work after 4 weeks, alosetron hydrochloride tablets is not likely to help you. You should stop taking it and call your doctor.

•

If you miss a dose of alosetron hydrochloride tablets, just skip that dose. Do
not take 2 doses the next time. Wait until the next time you are supposed to take it and then take your normal dose.

•

Follow the important instructions in the section “What is the most important information I should know about alosetron hydrochloride tablets?” about when you must stop taking the medicine and when you should call your doctor.

•

If you see other doctors about your IBS or side effects from alosetron hydrochloride tablets, tell the doctor who prescribed alosetron hydrochloride tablets.

6. What are the possible side effects of alosetron hydrochloride tablets?

Constipation is the most common side effect among women with IBS who take alosetron hydrochloride tablets. Some patients have developed serious bowel side effects while taking alosetron hydrochloride tablets. Read the section “What is the most important information I should know about alosetron hydrochloride tablets?” at the beginning of this Medication Guide for information about the serious side effects you may get with alosetron hydrochloride tablets.

This Medication Guide does not tell you about all the possible side effects of alosetron hydrochloride tablets. Your doctor or pharmacist can give you a more complete list.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Keep alosetron hydrochloride tablets and all medicines out of the reach of children.

8. General information about the safe and effective use of alosetron hydrochloride tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any questions or concerns about alosetron hydrochloride tablets, ask your doctor. Do not use alosetron hydrochloride tablets for a condition for which it was not prescribed. Do not share your medicine with other people. It may harm them.

Your doctor or pharmacist can give you more information about alosetron hydrochloride tablets that was written for healthcare professionals. You can also contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364.

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